Cancer Scans May Give False Picture of Genes Driving Dise

March 8 (Bloomberg) -- Cancer DNA tests give only a partial
picture of the genes driving the disease, according to a study
that throws cold water on the idea that scanning may quickly
lead to highly effective personalized treatments.

Multiple scans on kidney tumors determined that mutations in
each portion of the malignancy varied wildly, with only one-third of anomalies found in all parts, according to a report in
the New England Journal of Medicine.

If confirmed in other cancer types, the finding suggests
doctors and companies have only a limited ability to precisely
identify individual mutations that can be targeted with drugs,
since their tests are typically based on a single biopsy sample.
It may also explain why cancer becomes resistant to gene-targeted medicines, the U.K-based investigators said.

The result points to “a serious flaw in the imagined
future of oncology,” wrote Dan L. Longo, a cancer researcher
and deputy editor of the journal, in an accompanying editorial.

The researchers also performed an experimental prognostic
test that looked at levels of 110 genes on different samples
from a patient’s cancer, according to the report. When the test
was done on one part of a tumor, the disease was judged to have
a favorable prognosis. When the same scan was performed on
another section, the cancer had an adverse prognosis.

Devising nonstandard drug regimens based on the result of a
single gene test “should be applied with great caution until
more is known,” said Charles Swanton, an oncologist at Cancer
Research U.K. London Research Institute and the senior study
author. It could lead to harm if the patient gets prescribed a
drug that hits a gene mutation that turns out not to be present
in most of his tumor, he said.

Drug Resistance

The tumor variability could also explain why cancer becomes
resistant to gene-targeted drugs, according to Swanton. The
resistance mutations may be present from the start in some parts
of the tumor.

Barrett Rollins, chief scientific officer of the Harvard
University-affiliated Dana-Farber Cancer Institute in Boston,
said the finding doesn’t undercut current practice. While
variability is an issue, many cancers now respond to drugs
targeted at specific genetic features, he said.

“I’d be disappointed if the inference from this study is
that targeted therapies are useless,” Rollins said in a
telephone interview. “They’re not useless, they’re just not
useful enough.”

Cancer genetics is so complex that researchers may never
completely grasp it, Rollins said.

“Until we understand that whole universe of mutations,
we’ll have to treat what we find and test to see whether it
works,” he said.

‘Better Tools’ Needed

Brian Druker, the doctor and cancer researcher who helped
develop Gleevec, an early gene-based leukemia medicine made by
Novartis AG of Switzerland, said the analysis shows the need for
“better tools to identify cancer at earlier stages, when it is
far less complex.” Druker directs the Knight Cancer Institute
at the Oregon Health & Science University in Portland.

Personalized medicine “is going to be much harder than we
hoped,” said Andrew Futreal, a study co-author who is starting
a new job at the University of Texas MD Anderson Cancer Center
in Houston later this month, in a telephone interview.

“If you stick a needle in the right side of the tumor, you
could miss a key mutation in the left side,” he said.

One crucial question is whether lung cancer, breast cancer,
and other common cancer types are as variable as kidney cancer
was found to be, said Futreal, who did the research for the
tumor variability study in his previous job at the Wellcome
Trust Sanger Institute near Cambridge, England.

Ongoing large-scale cancer genome studies could provide
clearer answers in a year or two, he said.

Begun in 2010

The latest research began in 2010 when Swanton decided to
investigate previous research hinting that individual tumors
were genetically variable, he said. That could mean scanning
from a single biopsy wouldn’t produce results reliable enough to
guide therapy, he said.

Swanton and colleagues from other U.K. hospitals and
research institutes obtained tumor specimens that had been
removed from four advanced kidney cancer patients. They then
used DNA sequencing machines from San Diego-based Illumina Inc.
in the U.S. and other tests to evaluate genetic variability.

Instead of evaluating the DNA from just one tumor sample,
the typical practice today in hospitals, the researchers scanned
eight sections of the first patient’s primary tumor, and four
more sections from the patient’s metastases, malignant cells
that have escaped the main nesting area.

They found that only 40 of the 128 total gene mutations
found were present in all of the tumor samples.

‘Disturbing, Sobering’

“It was disturbing, sobering,” said Swanton, who is also
affiliated with University College London Hospital, in a
telephone interview. “There were overall more differences than
similarities between biopsies.”

A variety of DNA and chromosome tests on samples from three
other kidney cancer patients found the same pattern, he said.

In the future, researchers and physicians will have to
carefully validate cancer gene findings to make sure they
understand which mutations are likely found everywhere inside a
tumor, Swanton said.

Sequencers made by Illumina, Life Technologies Corp., of
Carlsbad, California, and other companies are allowing
scientists to analyze large swaths of DNA from numerous tumors
for the first time. Biotechnology companies are also selling and
developing tests that analyze tumor cell DNA to determine how
fast cancers will grow, or whether they may be treatable with
available medications.

‘Robust Tests’

Scientists at these companies are well aware that different
tumors in the same patient, and different parts of those tumors,
may harbor a variety of genetic mutations, said Michael Pellini,
president and chief executive officer of Foundation Medicine, a
cancer diagnostics company in Cambridge, Massachusetts.

“As an industry, we have to make sure we have very robust
tests,” he said in a telephone interview. Among other changes,
techniques for performing biopsies, the sampling of diseased
cells to characterize tumors and guide treatment, can be
improved to make sure cells that best represent the entire tumor
are analyzed, Pellini said.

Druker, the Gleevec developer, said the finding highlights
a problem that may soon be fixed.

“As the price of sequencing plummets, it will actually be
possible to sequence multiple areas of a tumor, or primary and
metastatic tumors from the same patient,” Druker said.

A second positive finding that can be drawn from the
report, he said, is that “while the primary tumor diverges,
there appears to be a convergence of mutations along specific
pathways. If we identify the right pathways to target we should
be able to use combination therapies to improve outcomes.”

Currently, Foundation Medicine charges $5,800 to search DNA
from patient tumors for cancer-related changes that may be
treated by existing drugs.